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With multinational cooperation, researchers have tracked down the cause of tau-negative frontotemporal dementia linked to chromosome 17q21. A pair of papers appearing in Nature online today, one from Mike Hutton’s group at the Mayo Clinic in Jacksonville, Florida, and another from Christine Van Broeckhoven and colleagues at the University of Antwerp in Belgium, reveal that mutations in the gene for the secreted growth factor progranulin (PGRN) are responsible for ubiquitin-positive frontotemporal dementia (FTD), the most common inherited form of the disease. Presented this week at the 10th International Conference on Alzheimer's Disease and Related Disorders in Madrid, Spain, this finding drew praise from independent scientists who called it a major advance in neurogenetics.

Finding the progranulin mutations solves a long-standing mystery—what causes familial FTD cases that are clearly linked to chromosome 17q21, but carry no detectable mutations in MAPT, the tau gene. As it turns out, the answer was close at hand. In what Hutton and colleagues call an “extraordinary coincidence,” the PGRN sits just 1.7 Mb away from MAPT, and despite the proteins having no apparent functional link, mutations in both genes each cause a clinically equivalent neurological disease.

The characteristic personality and behavior changes of FTD result from neuronal loss in the frontal and temporal regions of the brain. Nearly 10 years ago, mutations in the microtubule-associated protein tau were shown to cause familial FTD with parkinsonism linked to chromosome 17q21 (FTDP-17), a form of FTD characterized by tau-positive neuronal inclusions.

The majority of familial FTD cases do not show tauopathy, however, but display ubiquitin-immunoreactive neuronal inclusions that are mostly cytoplasmic but in some cases, nuclear. In multiple families, this form of FTD was linked to 17q21, the same region where the tau gene sits, but extensive searches yielded no mutations in that gene to account for the disease. That led several groups on an extensive search for mutations in other genes in a roughly 6-Mb critical region of 17q21. The Mayo researchers, working with collaborators from the University of British Columbia in Vancouver, Canada, and the University of Manchester in the U.K., focused on a large Canadian FTD family. After analyzing the coding sequences of 80 of the approximately 165 genes in the region, first authors Matt Baker, Ian Mackenzie, and Stuart Pickering-Brown hit pay dirt when they found an insertional mutation in the progranulin gene (PGRN).

Following the same strategy, first author Marc Cruts and the Van Broeckhoven team in Belgium ruled out MAPT mutations in a Dutch family, and then proceeded to identify a nonsense mutation in the progranulin gene. In all, the researchers identified 13 distinct progranulin deletions, insertions, and transitions in a total of nine families as well as in three unrelated patients. The mutations segregated with disease in families, and were never found among hundreds of unrelated controls tested. In a group of 43 Belgian patients with FTD, progranulin mutations were 3.5 times more frequent than tau mutations.

The progranulin mutations all introduced premature stop codons, and appeared to act as null alleles. The Mayo group showed that mutations resulted in nonsense-mediated RNA decay, and both groups documented lower levels of progranulin protein in lymphoblasts from affected family members.

In the brain, progranulin protein is present in cortical neurons and also in activated microglia in patients in FTD families, as well as in normal aged subjects and in people with Alzheimer disease. The presence of nuclear ubiquitin-positive inclusions appears especially associated with PGRN mutations, but neither those aggregates, nor the cytoplasmic inclusions showed any reactivity with progranulin antibodies. Their composition, therefore, remains an unsolved mystery.

Progranulin is widely expressed, and is involved in development, wound repair, and inflammation. Although the role of progranulin in neurons is unknown, the weight of evidence that PGRN haploinsufficiency causes FTD makes it clear that this factor is important for neuronal survival. Progranulin is known to activate signaling cascades including the MAP kinase and PI3 kinase pathways, both important for neuronal survival and function. On the flip side, overexpression of progranulin is involved in tumorigenesis, and high levels are found in glioblastomas.

Hutton and colleagues point out the similarity between progranulin and its role in FTD, and the secreted factor angiogenin, mutations in which have been linked to motor neuron loss in ALS (see ARF related news story). Angiogenin and progranulin have common functions, in that they both induce angiogenesis via vascular endothelial growth factor (VEGF), and tumorigenesis. Their deficiency may even result in a common neuropathology. Coauthors Ian Mackenzie and Howard Feldman showed previously that the ubiquitin-immunoreactive inclusions of FTD and motor neuron diseases display some similarities, suggesting they may spring from the same underlying events (Mackenzie and Feldman, 2005). The link of both factors to VEGF production, which itself has been shown to rescue motor neurons in a mouse model of ALS (see ARF related news story), opens up a world of new possibilities for further research and potential therapeutics.—Pat McCaffrey

Comments

The identification of progranulin mutations by Baker and colleagues is a major advance in our understanding of frontal temporal dementia (FTD). The work by both Baker and Cruts and their colleagues shows that loss of progranulin function is a major cause of FTD, at least in some populations. These findings are remarkable for several reasons: first, this is the first simple loss-of-function autosomal dominant disease; second, it suggests that the genetic linkage of two FTD loci with similar clinical features, but different pathologies, close to the same locus was just a confusing coincidence. Third, it will undoubtedly spawn a huge amount of effort to define the limits of the phenotype and to elucidate its precise function in the CNS. It will also be interesting to see whether other diseases with ubiquitin inclusions will share related pathogenic mechanisms.

These studies are spectacular advances in FTD research that open up new avenues for understanding mechanisms of FTLD-U. Notably, since progranulin proteins, or derivatives thereof, were not found in the ubiquitin inclusions of these FTLD-U disorders, it will be important to identify the ubiquitinated disease protein(s) that form these hallmark lesions of FTLD-U.

Both of these papers represent a significant discovery of a novel mutation on progranulin, a protein with no known CNS function. It is a known growth factor in vasculo and tumorigenesis, and it may turn out to have nerve growth factor properties as well; therefore, it is reasonable to postulate that a molecular deficit caused by its mutation could produce neurodegenerative disease such as frontotemporal dementia (FTD). We published the first chromosome 17-linked ubiquitin-positive family from Ontario in 2000 and the first intranuclear ubiquitin-positive inclusions in this and other families (1,2), but these genetic teams deserve credit for finding the mutation.

What is extraordinary is that progranulin is very close to the tau gene on chromosome 17, the known culprit in the mutated form in FTD linked to 17. How the two different genes interact, if at all, to cause a very similar illness is yet to be determined. The relationship of progranulin mechanisms to chromosome 9-linked cases and the valosin mutation with FTD and myopathy also deserves attention.